Primary biliary cirrhosis (PBC) is a liver specific autoimmune disease, characterized by portal tract lymphocytic infiltration, selective destruction of biliary epithelial cells and the presence of anti-mitochondrial antibodies (AMAs). Advances in the study of PBC have been hampered by its cryptic onset, and limitations in accessing human liver. We have taken advantage of a mouse transgenic for directed expression of a dominant negative form of transforming growth factor (TGF)-2 receptor type II (dnTGF2RII), under the direction of the CD4 promoter, and demonstrated that these mice develop several key features of PBC including spontaneous production of AMAs directed to PDC-E2, BCOADC-E2 and OGDC-E2, the same mitochondrial autoantigens recognized by patients. In addition, the epitope recognized by murine mitochondrial autoantibodies, similar to human patients with PBC, is the inner lipoyl domain and these autoantibodies also inhibit enzyme function. Moreover, dnTGF2RII mice have intense periportal inflammation composed of CD4 and CD8 cells as well as a serum cytokine profile analogous to that of human PBC. The murine construct studied herein is distinct from generic TGF-2-/- mice whose pathology is primarily ulcerative colitis. In contrast, dnTGF2RII mice survive over 6 months with only minimal ulcerative colitis and their dominant pathology is manifest in liver. Importantly, our data point away from initiation of autoimmunity by mechanisms such as molecular mimicry towards activation of an intrinsically self-reactive T cell repertoire in which necessary regulatory T cell influences are lacking. We propose to perform a detailed ontogenetic analysis of the immune system to define the kinetics by which specific lineages contribute to the disease process by utilizing dnTGF2RII mice. We will study the immunological aspects of the mouse model by analyzing the innate, humoral and cellular immune systems, liver lymphoid subpopulations, liver histopathology and kinetics of autoantibody production. We will also adoptively transfer isolated CD4+ and/or CD8+ T cells from dnTGF2RII mice to address T cell effector mechanisms involved in portal tract inflammation. In addition, we will determine the natural history and immunopathology in the absence of B cells. Our goal is to extend our pilot data to rigorously determine the validity of this model for human PBC and to enable focused future studies directed at mechanisms and potential therapy for PBC.